The broad, long-term objective of the project is to provide a solid foundation of knowledge about the cellular biology of cancer and aging. The first part of the project involves a critical analysis of the relationship between the limited lifespan of cells in culture and the long term replication of cells in the organism, particularly of the stem cells. This analysis will encompass the role of telomerase and telomeres in limiting the lifespan of human cells in culture and the relevance of these components to cell survival, differentiation and cancer in the organism. It will include consideration of the safety of the proposed use of artificially immortalized cells for therapy in humans. The second part of the project will compare the genetic stability of cells in culture, in the organism and in cancer. The role of tissue architecture in maintaining homeostasis in the organism will be extensively reviewed. The weakening of this top-down control with age will be considered in the origin of various chronic diseases associated with the aging process. The method is to use close, intensive reading of both the primary historical and the contemporary scientific literature relevant to the subjects. Emphasis will be placed on integrating the biological foundation of each field, often assumed but only superficially understood, with recent molecular findings to develop a more comprehensive, theoretical foundation of cellular change in cancer and aging. Several extensive reviews will be published m leading scientific journals to be followed eventually by unification into a monograph. Amalgamation of these and related subjects in a comprehensive volume is contemplated.